Abstract
The mature human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer is produced by proteolytic cleavage of a precursor and consists of three gp120 exterior and three gp41 transmembrane subunits. The metastable Env complex is induced to undergo conformational changes required for virus entry by the binding of gp120 to the receptors, CD4 and CCR5/CXCR4. An isoleucine-to-proline change (I559P) in the gp41 ectodomain has been used to stabilize soluble forms of HIV-1 Env trimers for structural characterization and for use as immunogens. In the native membrane-anchored HIV-1BG505 Env, the I559P change modestly decreased proteolytic maturation, increased the non-covalent association of gp120 with the Env trimer, and resulted in an Env conformation distinctly different from that of the wild-type HIV-1BG505 Env. Compared with the wild-type Env, the I559P Env was recognized inefficiently by polyclonal sera from HIV-1-infected individuals, by several gp41-directed antibodies, by some antibodies against the CD4-binding site of gp120, and by antibodies that preferentially recognize the CD4-bound Env. Some of the gp120-associated antigenic differences between the wild-type HIV-1BG505 Env and the I559P mutant were compensated by the SOS disulfide bond between gp120 and gp41, which has been used to stabilize cleaved soluble Env trimers. Nonetheless, regardless of the presence of the SOS changes, Envs with proline 559 were recognized less efficiently than Envs with isoleucine 559 by the VRC01 neutralizing antibody, which binds the CD4-binding site of gp120, and the PGT151 neutralizing antibody, which binds a hybrid gp120-gp41 epitope. The I559P change completely eliminated the ability of the HIV-1BG505 Env to mediate cell-cell fusion and virus entry, and abolished the capacity of the SOS Env to support virus infection in the presence of a reducing agent. These results suggest that differences exist between the quaternary structures of functional Env spikes and I559P Envs.
Highlights
Human immunodeficiency virus (HIV-1) entry into the host cell is mediated by the viral envelope glycoproteins (Envs), which are derived by proteolytic cleavage of a trimeric gp160 Env precursor [1,2,3]
Recombinant luciferase-expressing HIV-1 viruses bearing the full-length wt, I559P or S375W mutant Envs were spinoculated onto Cf2Th cells expressing human CD4 and CCR5 to assess the ability of the Envs to support virus entry [57,59]
These results indicate that the I559P change completely compromises the function of the HIV-1BG505 Env
Summary
Human immunodeficiency virus (HIV-1) entry into the host cell is mediated by the viral envelope glycoproteins (Envs), which are derived by proteolytic cleavage of a trimeric gp160 Env precursor [1,2,3]. The metastable Env trimer undergoes conformational changes upon binding of gp120 to the receptors, CD4 and CCR5/CXCR4, that promote the fusion of the viral and target cell membranes by gp41 [1,4,5,6,7,8,9,10,11,12,13,14,15,16,17]. The soluble gp140 SOSIP.664 structures differ from cryo-EM maps of unliganded, proteolytically mature Env trimers derived from virions or uncleaved Env trimers from cell surfaces [40,41,42,43]. Env crystals unexpectedly resembles the CD4-bound conformation,[36,37,38,44] These observations suggest possible differences in conformation between the soluble gp140 SOSIP.664 trimers and the unliganded functional Env spike on the surface of infected cells and virions. We investigate the conformation of the gp120 core in the HIV-1BG505 Env by studying the phenotypes of a mutant, S375W, that predisposes gp120 to assume the CD4-bound state
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